The present invention relates to substituted 2-pyrrolidin-2-yl-[1,3,4]-oxadiazole compounds, to methods for their production, to pharmaceutical compositions containing these compounds and to the use of these substances for producing pharmaceutical compositions, preferably for the treatment of depression, and to methods of treating depression.
Depression is an affectivity disorder, in which a depressive syndrome predominates, depression being associated with a depressive mood or indicating a sad disposition. The anti-depressants used for treatment are also important adjuvants for pain therapy (van Schayck et al., MMP 1998, Vol. 21, issue 10, 304–313; Jung et al., J. Gen. Intern. Med. 1997, 12/6, 384–389; Onghena and Van Houdenhove, Pain 1992, 49, 205–219; Feuerstein, Der Schmerz 1997, 11, 213–226; Rowbotham, The Pain Medicine Journal Club 1997, 3/3, 119–122), in particular for chronic pain conditions, as the prolonged burden of pain may lead to a depressive mood in the patient. This is particularly frequently the case in patients suffering from pain with cancer (Berard, Int. Med. J. 1996, 3/4, 257–259). As there have previously been no painkillers with a clinically relevant anti-depressive active component, the anti-depressants have to be added as a medication supplementary to the analgesic dose. As patients with chronic pain frequently require a large number of different medicines, the additional dose of the anti-depressant is a further burden to the organism. For this reason and to increase compliance, an analgesically effective substance with an anti-depressive active component would be particularly advantageous.
The basis of the anti-depressive efficacy is the inhibition of serotonin re-uptake.
Various substituted 2-pyrrolidin-2-yl-[1,3,4]-oxadiazole derivatives are known from the literature. Common to all of them is the fact that they are used for the treatment of neuronal diseases.
The synthesis of substituted 2-pyrrolidin-2-yl-[1,3,4]-oxadiazole derivatives has already been described by Borg et al. (J. Org. Chem. 1995, 60, 3112–3120), natural amino acids being used as the starting material and dehydration of diacylhydrazines taking place, and by Brain et al. (Synlett 2001, No. 3, 382–384), the cyclodehydration of 1,2-diacylhydrazines being carried out under microwaves using a polystyrene-supported dehydration agent. These syntheses are solid phase syntheses.
WO 01/04116 describes another way of synthesising pyrrolidine or piperidine derivatives for the treatment and prevention of neuronal diseases.
JP 2001247569 also describes the production of pyrrolidine or piperidine derivatives and their use for the prophylaxis and/or treatment of diseases, which are accompanied by damage to the nerves or neurodegeneration.